PROJECT SUMMARY There is an incredible, desperate need to find new biomarkers to improve our ability to personalize cancer therapy, to identify responders, and, perhaps more importantly, to identify those that will experience toxicity from treatment in the context of response and non-response. This need has led to Provocative Question #8, asking us to investigate: What are the predictive biomarkers for the onset of immune-related adverse events associated with checkpoint inhibition, and are they related to markers for efficacy? While there have been several tumor-acquired mutations applied as biomarkers for targeted chemotherapies, no such biomarkers have been identified that can predict toxicity to therapy. Immune-related adverse events are likely related to the complex host-specific response to therapy, suggesting that the host's tumor may not be the best source of biomarkers, but that instead germ-line biomarkers, that are also present in all the patient's cells, including their immune cells, could be a much more viable source. While global approaches to study normal DNA have been applied to find germline biomarkers, they do not purport to identify functional biomarkers, only tagging SNPs that may be associated with functional biomarkers elsewhere in the DNA. There is growing evidence that germline microRNA (miRNA) disrupting mutations are in fact functional biomarkers identifying patients with altered stress responses to cancer therapy, which are not currently included in normal DNA analyses. In this proposal, the goal is to validate the predictive power of this new class of miRNA-based biomarkers, in two clinical trials of patients with NSCLC or HNSCC, treated with immune therapies. The final confirmed panel of functional biomarkers will be further correlated with other biomarkers found to help identify patients with toxicity to checkpoint therapy. Results from this proposal could allow the identification of patients who have genetically unique immune system circuitry resulting in an altered response to immune modulating therapies, which will allow significant progress towards answering PQ#8.